adenosine-5--(n-ethylcarboxamide) and 3-5-dihydroxyphenylglycine

Co-activation of group I metabotropic glutamate (mGlu) receptors and adenosine receptors resulted in an augmented cyclic AMP response in primary cultures of rat striatal neurones. L-glutamate and the selective group I agonist, (S)-dihydroxyphenylglycine (S-DHPG) evoked concentration-dependent potentiations of cyclic AMP accumulation stimulated by the adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), with EC50 values of 3.41+/-0. 39 and 5.69+/-1.64 microM, respectively, and maximal augmentations of approximately 350% at concentrations of 100 microM. The S-DHPG potentiation was inhibited by group I mGlu receptor antagonists and a protein kinase C inhibitor, Ro 31-8220, implicating products of PI hydrolysis in this effect. Furthermore, L-glutamate and S-DHPG stimulated PI hydrolysis in striatal neuronal cultures with similar EC50 values to those observed for the augmentation of NECA cyclic AMP responses (5.19+/-1.18 and 3.78+/-1.42 microM, respectively). In situ hybridization and immunofluorescence techniques indicate that group I mGlu receptor-evoked potentiations are likely to be mediated via mGlu5 receptors, which are expressed at high levels in these cultures. In contrast to cross-chopped slices of neonatal rat striatum, of equivalent age, the group II mGlu receptor agonist, (2S, 2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) was without effect on NECA- or forskolin-stimulated cyclic AMP responses in primary striatal neuronal cultures. This lack of effect might be due to a low level of expression of group II mGlu receptors in cultured striatal neurones.

Topics: Adenosine-5'-(N-ethylcarboxamide); Animals; Autoradiography; Cells, Cultured; Corpus Striatum; Cyclic AMP; Excitatory Amino Acid Agonists; Fluorescent Antibody Technique; Glutamic Acid; Glycine; Hydrolysis; In Situ Hybridization; Neurons; Phosphatidylinositols; Rats; Receptors, Metabotropic Glutamate; Resorcinols

LY354740 is a highly potent and selective agonist for recombinant Group II mGlu receptors (mGlu2 and mGlu3), which has anxiolytic and drug withdrawal alleviating properties when administered systemically in rats and mice. The modulation of second messengers by LY354740 in rat brain tissues was investigated to understand the cellular basis for the pharmacological and potential therapeutic actions of LY354740. LY354740 potently decreased forskolin-stimulated cAMP formation in slices of the adult rat hippocampus (EC50=22+/-3 nM) in a stereoselective manner. LY354740 (at 1 microM) greatly (>90%) suppressed forskolin-stimulated cAMP in the cerebral cortex, hippocampus, and striatum, while producing only partial suppression (about 50%) in midbrain regions and olfactory bulb, and no significant cAMP alterations in the cerebellum and brainstem regions. Inhibition of forskolin-stimulated cAMP formation was antagonized by (+)-alpha(-methyl-4-carboxyphenylglycine [(+)MCPG], a competitive mGlu receptor antagonist. LY354740 did not alter phosphoinositide hydrolysis in the rat hippocampus per se, but potentiated stimulation of phophoinositide hydrolysis by the Group I mGlu receptor selective agonist 3,5-dihydroxyphenylglycine (DHPG) or stimulation of cAMP formation by the adenosine receptor agonist 5'-N-ethylcarboxamideoadenosine (NECA). These data indicate that LY354740 is a highly potent, efficacious, and selective Group II mGlu receptor (mGlu 2/3) agonist in the rat brain. The potent, stereoselective, and brain region selective actions of LY354740 on mGlu receptor linked second messenger systems likely underlie the in vivo potency and stereoselectivity of this compound in animal models.

Topics: Adenosine-5'-(N-ethylcarboxamide); Animals; Brain; Bridged Bicyclo Compounds; Cyclic AMP; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycine; Hydrolysis; Male; Phosphatidylinositols; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Resorcinols; Second Messenger Systems; Stereoisomerism; Vasodilator Agents